Introduction
Various risk prediction models are used to predict atherosclerotic cardiovascular disease (ASCVD) in asymptomatic populations. Prevention of ASCVD requires timely and precise identification of individuals at increased risk so that lifestyle or drug interventions can be recommended. Unfortunately, large systematic reviews only show limited usefulness of most risk prediction models, since they are often not externally validated and there is substantial heterogeneity among predictors and outcome [1, 2]. More importantly, risk prediction models as a whole overestimate risk [3]. This has been extensively demonstrated by several large prospective cohort studies, with follow-up periods of 10 years, showing that overestimation of current risk prediction models is more common than underestimation [3, 4], although underestimation is of importance in younger age groups, individuals of low social economic background or certain ethnic groups. One way to address overestimation is by updating the current risk prediction models, such as SCORE2 [5]. On the other hand, one might also improve risk prediction by adding new markers to existing models, such as the coronary artery calcium score (CACS) derived from non-contrast cardiac CT.
CACS gives an estimate of the underlying coronary atherosclerosis, which reflects the impact of all risk factors, known and unknown—and the vulnerability of the individual to these risk factors—on the arterial wall [6]. As such, CACS may give an improved estimate of ASCVD risk [7]. However, the position of CACS for risk prediction is still debated. Important issues discussed below are the positive and negative predictive values; how to position CACS within the current risk prediction models for the asymptomatic individual or as screening tool for the population; its cost-effectiveness; issues regarding therapy; and the potential future role of coronary CT angiography (CCTA) in asymptomatic individuals.
Current role of CACS in predicting CV disease
Positive predictive value: adding CACS to current cardiovascular disease risk prediction models
CACS provides incremental value above and beyond current ASCVD risk prediction models, as was concluded in a 2022 meta-analysis of 6 prospective cohort studies comprising almost 18,000 individuals followed for almost 10 years [8]. In addition, McClelland et al. investigated and externally validated a new risk prediction model including CACS [9]. They showed, in two independent validation cohorts, a significant improvement in risk prediction (C-statistics) from 0.7 to around 0.8, when using the new risk equation including CACS. Although the net reclassification improvement (NRI) is not the best way to analyse the incremental value of a marker [10], several studies showed a substantial category-based NRI of 14–32% when adding CACS to different risk prediction models [11–13]. A recent prospective study showed the discriminatory power of CACS beyond SCORE2, which is the risk scoring algorithm included in the most recent ESC guideline: C index for cardiovascular events was 0.61 for SCORE2, and 0.75 when CACS was added [14]. Therefore, there is an abundance of evidence that CACS improves the risk prediction of cardiovascular disease in primary prevention among asymptomatic individuals.
Negative predictive value: the role of CACS in ruling out significant CAD (‘the power of zero’)
Continuing evidence shows that the absence of coronary calcification (CACS 0) in asymptomatic individuals is related to a very low risk of ASCVD, even in individuals with a high risk according to the currently used conventional risk prediction models. A systematic review of 13 studies comprising 64,873 asymptomatic individuals, followed for around 4 years, showed that 40% had a CACS 0, and that the 10-year CVD risk of these individuals was only 0.56% [15]. Two other independent cohorts, comprising 16,529 asymptomatic individuals followed for a longer period of 10 [16] or 15 [17] years, both showed that in individuals with CACS 0, the 10-year CVD risk was on average only 3.2%. In all studies the low 10-year ASCVD risk was independent of the presence of traditional risk factors. In fact, in one of these studies, asymptomatic individuals with CACS 0 had an even lower 10-year CVD risk (2.8%) than individuals who were categorised in the low-risk group (meaning absence of traditional risk factors), assessed by current risk models (3.3%) [16]. In addition, in one of the largest cohorts, comprising 44,052 asymptomatic individuals followed for an average of 6 years, individuals with more than three risk factors (e.g. diabetes, dyslipidaemia, hypertension, smoking) and CACS 0 had a 10-year ASCVD mortality risk of only 2% [18]. This indicates that even in asymptomatic individuals classified as (very) high risk because of the presence of multiple risk factors [16, 17, 19], type 2 diabetes [19] or familial hypercholesterolaemia [20], the absence of coronary calcium is associated with an extremely low ASCVD event rate.
Limitations of CACS
There are some limitations to consider when using cardiac CT for cardiovascular risk prediction, such as radiation exposure, healthcare costs and incidental non-cardiac findings. All modern scanners can now acquire a cardiac CT for CACS with radiation doses < 1 mSv [21], a radiation exposure that is much lower than the annual background radiation. The cost of a non-contrast cardiac CT also depends on the time required for calculating the CACS and assessing the scan for incidental findings. Costs can be reduced by automatically calculating CACS with the current software and omitting assessment for incidental findings. On the other hand, one could argue that relevant incidental non-cardiac findings are not a costly burden but a blessing in disguise, such as early lung carcinoma detection. Further studies are needed to adequately assess cost-effectiveness, taking into account incidental non-cardiac findings. Finally, CACS cannot rule out the presence of non-calcified atherosclerotic plaque and possible high-risk plaque features. However, all studies with long-term follow-up show that the negative predictive value of CACS 0 for cardiovascular events is excellent in asymptomatic individuals. Furthermore, Mortensen et al. showed in 23,143 individuals who underwent CACS and CCTA that a CACS of 0 resulted in a very low event rate of 6.9 per 1000 person-years, regardless of whether there was no plaque, purely non-calcified plaque or even non-calcified plaque with > 50% stenosis [22].
Positioning of CACS in the Dutch guideline on CVRM
Conventional risk prediction models based on traditional risk factors are commonly used in a case-finding method at the general practitioners (GPs) office, without systematic screening on a population level. In view of the limited accuracy of risk prediction models and the strong predictive value of CACS for ASCVD, screening by using CACS may improve risk prediction. However, this approach is currently not included in the cardiovascular risk management (CVRM) guideline; the focus is on the potential value of CACS to assist in decision-making regarding preventive medication around treatment thresholds for the risk factor-based risk score (Fig. 1). CACS has clearly shown its added value in risk prediction in asymptomatic individuals, at least those aged between 50 and 70 years (but maybe even a broader range) with intermediate or maybe even high CV risk based on current risk prediction models, but most guidelines do not yet recommend CACS for risk management. This is partly due to the fact that the cost-effectiveness of adding CACS to risk prediction models has not been convincingly established [23]. The Dutch CVRM guideline is currently being updated and will be published in 2024. The position of CACS as a diagnostic tool for reclassification of cardiovascular risk in primary prevention will be revised. The previous guideline (2019) stated that if CACS is available one can consider to take it into account in individuals in whom there is doubt as to whether to start preventive therapy [24]. Indeed, knowing the CACS is high increases medication adherence [25]. The new CVRM guideline advises to consider determining CACS in individuals aged 50–70 years if a discussion about whether to initiate drug treatment does not yield a decision. Importantly, nowadays nearly all Dutch hospitals offer CT for CACS evaluation, and in some regions GPs can already order a CT-CACS, without referral to a medical specialist, making CT more accessible.
Fig. 1 [Images not available. See PDF.]
Infographic: Stepped approach with coronary calcium score. CACS coronary artery calcium score; p75 75th percentile; no CACS recommended in low CV-risk group, although 4% have significant CAC [42]
CACS screening for primary prevention
So far, there is no evidence from randomised controlled trials (RCTs) that screening strategies based on CACS improve prognosis. It is important to note that this level of evidence is also lacking for the current risk prediction models, as highlighted in the 2021 ESC Guideline on Prevention [26]. The only two RCTs, the St Francis Heart study [27], and DANCAVAS [28], have not yet shown a clear benefit for treatment according to a population-based screening approach with CACS. However, in a sub-analysis of the St Francis Heart study, individuals with a positive family history of CVD and CACS > 80th percentile had a 45% reduction in events in the cholesterol-lowering arm as compared with placebo [27]. The DANCAVAS study, a population-based screening study comprising 46,611 men, suggested possible benefit for a broad cardiovascular screening approach including CT, but did not reach statistical significance for the primary endpoint of all-cause mortality after a follow-up of 5.6 years (HR 0.95, 95% CI 0.90–1.00, p = 0.06). Importantly, the primary endpoint reached borderline significance, while the study was powered for a 10-year follow-up [28]. On the other hand, in a prespecified subgroup analysis, younger participants (65–69 years) had more benefit from screening than older individuals (> 70 years). Currently, the Dutch ROBINSCA (Risk or benefit in screening for cardiovascular diseases) trial is being conducted [29]. This trial is evaluating men aged 45–74 years and women aged 55–74 years, with at least one risk factor, comparing a CACS-based strategy (intervention arm) with usual GP care (control arm). Management in the two intervention arms is evidence based. Over 43,000 individuals were included and currently 5‑year outcomes are awaited.
Interpretation and implication of CACS
When and how to treat or not to treat based on CACS in asymptomatic individuals for primary prevention of ASCVD is still debated. Despite the lack of evidence from major RCTs, observational data have shown that a significantly elevated CACS, ≥ 100 or ≥ 75th age, sex and ethnicity corrected percentile, causes a sufficiently high risk to consider cholesterol-lowering therapy [16, 17]. Therefore, the combined European and American CVRM guidelines advise to consider cholesterol-lowering therapy if CACS is significantly elevated and to consider withholding cholesterol-lowering therapy if CACS is 0 [26, 30].
It is unknown whether there is a threshold for CACS above which aspirin therapy should be initiated. It is currently not recommended to prescribe aspirin in primary prevention because of the increased risk of bleeding [31]. On the other hand, randomised trials on aspirin use did not take into account CACS, therefore we do not know whether the individuals who benefited from aspirin therapy in these trials might have been the ones with an increased CACS. However, incorporating CACS in an aspirin-prescription decision-making tool, based on the MESA study, suggested that individuals with CACS ≥ 100 would benefit from treatment with aspirin, regardless of their risk status according to current risk prediction models (estimated 5‑year number needed to treat: 173 for low-risk individuals; 92 for high-risk individuals and 442 for a major bleed) [32].
Reclassification to a lower ASCVD risk based on CACS 0, and withholding preventive treatment
ASCVD risk prediction should not be viewed as a static process. Risk of ASCVD evolves over the years, not only because individuals get older, but also because risk factors evolve. Therefore, it is important to realise that when CACS is 0, it needs to be repeated in the coming years. This is in line with the 2018 ACC/AHA cholesterol guidelines, which emphasise the clinical importance of CACS 0, and state that it is reasonable to withhold cholesterol-lowering therapy and, in most individuals, reassess risk with CACS in 5 to 10 years [30]. In certain very high-risk subgroups, such as familial hypercholesterolaemia, guidelines advise to continue cholesterol-lowering therapy in patients with a CACS of 0, considering their very high lifetime risk of ASCVD [33]. On the other hand, two independent prospective cohort studies showed that individuals with familial hypercholesterolaemia and CACS 0, still had a very low 10-year event rate of 0–1.2% [20, 34]. Therefore, CACS could help increase precision in familial hypercholesterolaemia patients and could help to reduce costs related to more intensified cholesterol-lowering regimens. Finally, although multiple studies comprising in total 4248 individuals with CACS 0 followed for 3 to 10 years showed that the warranty period for the development of any CAC is 3 to 7 years [35, 36], another study showed that only 2% of individuals with CACS 0 at baseline progressed to CACS > 50 in 5 years [36]. Furthermore, only individuals with a positive, low CACS level of 1–100 at baseline progressed to a substantial risk (e.g. > 7.5%, in 10 years) for which cholesterol-lowering medication is recommended [16].
Cost-effectiveness of CACS as part of cardiovascular risk prediction
One of the reasons why CACS currently has no basis in risk prediction has to do with the fact that the cost-effectiveness analyses in the primary prevention context have so far shown conflicting results [23, 37]. Critical factors that drove the conclusions in all these studies were the costs associated with cholesterol-lowering medication, the rating of side effects from cholesterol-lowering medications and the general desire to avoid lifelong preventive therapy. In the most recent cost-effectiveness analysis by Hong et al. [23], outcomes were similar for risk prediction based on the addition of CACS or based on the 2013 ACC/AHA guidelines [38] only. They analysed the addition of CACS in the intermediate-risk group in which only 11.4% had a CACS elevated enough to start cholesterol-lowering therapy. Although for the intermediate-risk group it did not seem cost-effective to add CACS to risk prediction models, it did result in less patients receiving preventive therapy, namely 44% of individuals considered or recommended for cholesterol-lowering therapy had CACS of 0. Therefore, as a rule-in strategy CACS does not seem to be cost-effective, but as a rule-out strategy it might be. The authors concluded that cost-effectiveness analyses should not be the only criterion for clinical decision-making, but that a shared decision-making model is similarly important for clinicians, patients and policy-makers.
Future perspectives of CT for screening CAD and CVRM
CACS can help in a more accurate reclassification of cardiovascular risk prediction and will be used as such more often in the future. Multiple studies, comprising 25,370 asymptomatic individuals, have shown that in almost one-third of individuals recommended for cholesterol-lowering medication, risk was overestimated based on current risk prediction models, since they had CACS 0, translating into an extremely low ASCVD event rate of less than 1% in 10 years [16, 17, 39, 40]. Similarly, in a Dutch population around one-third of individuals recommended for cholesterol-lowering therapy had CACS 0 [40]. Interestingly, there were also substantial differences between men and women with almost 50% of women recommended for cholesterol-lowering therapy having CACS 0. Additional biomarkers have also been proposed for risk prediction. A prospective cohort study of almost 6000 individuals, followed for 7 years, evaluated the predictive value of multiple biomarkers such as N‑terminal fragment of prohormone B‑type natriuretic peptide (NT-proBNP), von Willebrand factor, fibrinogen, leucocyte count, homocysteine, uric acid, chronic kidney disease, peripheral artery disease, C‑reactive protein, pulse wave velocity, intima media thickness and CACS [41]. They concluded that CACS best improved risk prediction when added to the Framingham risk score, with an increase in c‑statistic of 0.05. Another biomarker to consider is lipoprotein a (Lp(a)), which has shown consistent epidemiological and genetic evidence that increased values are associated with higher ASCVD risk [42]. When Lp(a) was compared with CACS, individuals with CACS 0 and elevated Lp(a) had a similar low risk of ASCVD as individuals with CACS 0 and low Lp(a) levels [43].
Potential role of CCTA in estimation of cardiovascular risk in asymptomatic individuals
Important benefits of CCTA over CACS are the possibility to characterise plaque composition and characteristics, and the opportunity to evaluate response to preventive therapy. It is unclear if CCTA is useful in the general population considered for primary prevention. Studies in symptomatic individuals have shown important prognostic value for CCTA for atherosclerosis quantification [44] but not in asymptomatic populations. This is currently being investigated in several RCTs: SCOT-HEART2 (NCT03920176; n = 6000), DANE-HEART (NCT05677386; n = 6000) and TRANSFORM (NCT06112418; n = 7500).
The Society of Cardiovascular Computed Tomography (SCCT) 2021 expert consensus makes the following recommendations for CCTA in asymptomatic individuals: (1) it is rarely appropriate to perform CCTA in low- and intermediate-risk populations; (2) it may be appropriate to perform CCTA in selected high-risk populations, especially if they have a high probability of substantial non-calcified plaque [45]. Examples of such selected groups are young patients with familial hypercholesterolaemia [34] and individuals with a hazardous occupation, such as pilots and individuals with a high cardiovascular risk [46]. The NATO HFM-251 Occupational Cardiology in Military Aircrew working group recommends enhanced screening with CACS alone or combined with CCTA in aircrew who are identified with increased risk using a conventional risk calculator and resting ECG. In addition, the SCCT recommends CCTA: (1) as an appropriate alternative to invasive angiography and other non-invasive tests before non-coronary surgery; (2) to exclude CAD in patients with suspected non-ischaemic cardiomyopathy; (3) as an appropriate alternative to invasive angiography for coronary allograft vasculopathy in patients after heart transplantation [45].
Although there is no conclusive evidence, there are other groups that may benefit from additional CCTA. For instance, women with preeclampsia, since according to the current Dutch guidelines they carry the highest risk for ASCVD of all female specific risk factors [47]. Furthermore, various studies have shown a higher prevalence of CACS ≥ 100 and (calcified) plaque on CCTA in athletes in comparison with less active controls. Higher CACS may not represent a higher CV risk in athletes, but absence of CAC and plaque on CCTA is always better than any CACS or coronary plaque [48].
Rapid development of AI-supported algorithms to automatically quantify plaque volumes and high-risk plaque characteristics from CCTA can help to assess important prognostic markers for future cardiovascular events [49]. In conjunction, developments in genetic risk assessment and blood omics approaches, such as proteomics or lipidomics, may enable a personalised multidimensional ‘one-stop shop’ approach in ASCVD risk prediction in the near future.
Conclusion
CACS has a role in CVRM management of asymptomatic individuals, at least those between 50 to 70 years with intermediate ASCVD risk, based on current risk prediction models using traditional risk factors. CACS improves risk prediction, although there are conflicting results on cost-effectiveness. Current guidelines recommend to consider cholesterol-lowering therapy in case of CACS ≥ 100 or ≥ 75th percentile. The absence of CAC reflects an extremely low 10-year risk of ASCVD and could be used to withhold cholesterol-lowering therapy for 5 to 10 years, but this is subject to future research. Currently, adding CCTA may only be considered in selected high-risk asymptomatic persons.
Acknowledgements
We would like to thank the following general practitioners for carefully reading the manuscript and for giving constructive comments, which substantially improved the quality of our manuscript:
Prof. Dr. E. P. Moll van Charante, Department of General Medicine, Amsterdam University Medical Center, location AMC, Amsterdam; Dr. D. Rijlaarsdam-Hermsen, General Physician, Rotterdam; Dr R. Willemsen, Department of General Medicine, University Maastricht, Maastricht.
They were asked their opinion because most of the asymptomatic individuals mentioned in this article will presented to General Practitioners.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
Conflict of interest
S.-J. Pinto-Sietsma, B.K. Velthuis, N.S. Nurmohamed, R. Vliegenthart and F.M.A.C. Martens declare that they have no competing interests.
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Abstract
Several risk prediction models exist to predict atherosclerotic cardiovascular disease in asymptomatic individuals, but systematic reviews have generally found these models to be of limited utility. The coronary artery calcium score (CACS) offers an improvement in risk prediction, yet its role remains contentious. Notably, its negative predictive value has a high ability to rule out clinically relevant atherosclerotic cardiovascular disease. Nonetheless, CACS 0 does not permanently reclassify to a lower cardiovascular risk and periodic reassessment every 5 to 10 years remains necessary. Conversely, elevated CACS (> 100 or > 75th percentile adjusted for age, sex and ethnicity) can reclassify intermediate-risk individuals to a high risk, benefiting from preventive medication. The forthcoming update to the Dutch cardiovascular risk management guideline intends to re-position CACS for cardiovascular risk assessment as such in asymptomatic individuals. Beyond CACS as a single number, several guidelines recommend coronary CT angiography (CCTA), which provides additional information about luminal stenosis and (high-risk) plaque composition, as the first choice of test in symptomatic patients and high-risk patients. Ongoing randomised studies will have to determine the value of atherosclerosis evaluation with CCTA for primary prevention in asymptomatic individuals.
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Details
1 Amsterdam University Medical Center, Department of Epidemiology and Data Science, Amsterdam, The Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010); Amsterdam University Medical Center, Department of Vascular Medicine, Amsterdam, The Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010)
2 University Medical Center Utrecht, Department of Radiology, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000 0000 9012 6352)
3 Amsterdam University Medical Center, Department of Vascular Medicine, Amsterdam, The Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010); Amsterdam University Medical Center, Department of Cardiology, Amsterdam, The Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010)
4 University Medical Center Groningen, Department of Radiology, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598)
5 Amsterdam University Medical Center, Department of Cardiology, Amsterdam, The Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010)